Effects of sex and estrous cycle on sleep and cataplexy in narcoleptic mice

Abstract

Narcolepsy type 1 (NT1) is a rare neurology disorder caused by the loss of orexin/hypocretin neurons. NT1 is characterized by excessive daytime sleepiness, sleep and wake fragmentation and cataplexy. These symptoms have been equally described in both women and men, although influences of gender and hormonal cycles have been poorly studied. Unfortunately, most studies with NT1 pre-clinical mouse models, use only male mice to limit potential variations due to the hormonal cycle. Therefore, whether gender and/or hormonal cycles impact the expression of narcoleptic symptoms remains to be determined. To address this question, we analyzed vigilance states and cataplexy in 20 female and 17 male adult orexin knock-out narcoleptic mice, with half of the females being recorded over multiple days. Mice had access to chocolate to encourage the occurrence of cataplectic episodes. A vaginal smear was performed daily in female mice to establish the state of the estrous cycle of the previous recorded night. We found that vigilance states were more fragmented in males than females, that females had less paradoxical sleep (p=0.0315) but more cataplexy (p=0.0375). Interestingly, sleep and wake features were unchanged across the female estrous cycle, but the total amount of cataplexy was doubled during estrus compared to other stages of the cycle (p=0.001), due to a large increase in the number of cataplexy episodes (p=0.0002). Altogether these data highlight sex differences in the expression of narcolepsy symptoms in orexin knock-out mice. Notably, cataplexy occurrence was greatly influenced by estrous cycle. Whether it is due to hormonal changes would need to be further explored.

Positive memory increases cataplexy-like behaviors in narcolepsy mice as revealed using conditioned place preference test

“…Recent studies showed a gender difference in the number and duration of cataplexy in orexin neuron-ablated mice [ 16 , 17 ] and orexin peptide knockout mice [ 18 ]. However, we did not find any gender difference not only in the place preference score (Fig.…”

Estradiol-dependent hypocretinergic/orexinergic behaviors throughout the estrous cycle

“…These results suggest that E2 recruits hypothalamic orexin neurons to mediate wakefulness (Deurveilher et al 2008), exemplifying a positive association between these two neuromodulatory systems when it comes to sleep promotion. Another study showed that when orexin function is knocked out to produce a narcolepsy type 1 phenotype, females of this mouse strain display normal estrous cycling despite the severity of their catalepsy being phase-dependent (Arthaud et al 2022). In the absence of orexin activity, longer and more frequent cataplectic episodes occur during estrus when both E2 and progesterone levels have dropped (Arthaud et al 2022).…”

“…Another study showed that when orexin function is knocked out to produce a narcolepsy type 1 phenotype, females of this mouse strain display normal estrous cycling despite the severity of their catalepsy being phase-dependent (Arthaud et al 2022). In the absence of orexin activity, longer and more frequent cataplectic episodes occur during estrus when both E2 and progesterone levels have dropped (Arthaud et al 2022). Interestingly, vigilance, time awake, slow-wave sleep, and paradoxical sleep do not change across the estrous cycle in these knockout mice (Arthaud et al 2022) despite these sleep-wake characteristics being phase-dependent in wild-type animals (Schwierin et al 1998;Swift et al 2020;Arthaud et al 2022).…”

“…In the absence of orexin activity, longer and more frequent cataplectic episodes occur during estrus when both E2 and progesterone levels have dropped (Arthaud et al 2022). Interestingly, vigilance, time awake, slow-wave sleep, and paradoxical sleep do not change across the estrous cycle in these knockout mice (Arthaud et al 2022) despite these sleep-wake characteristics being phase-dependent in wild-type animals (Schwierin et al 1998;Swift et al 2020;Arthaud et al 2022). Thus, some aspects of arousal and wakefulness such as catalepsy rely on orexin/estrous cycle signaling, but not all (Schwierin et al 1998;Swift et al 2020;Arthaud et al 2022).…”

“…Preceding their clinical approval for use in sleep disorders such as insomnia (reviewed in Muehlan et al 2020), both selective orexin receptor antagonists (SORAs) and dual orexin receptor antagonists (DORAs) were and continue to be tested in animal demonstrations of abnormal feeding like binge eating (Haynes et al 2002;Piccoli et al 2012), substance-use disorder (reviewed in Perrey and Zhang 2020), and stress-induced anxiety-like behaviors (Vanderhaven et al 2015;Salvadore et al 2020). The orexin system functionally interacts with the HPG axis (reviewed in Silveyra et al 2010) such that orexin-mediated behaviors are modulated in part by estrous cycle phases (Deurveilher et al 2008;Arthaud et al 2022;Funabashi et al 2009;Zhou et al 2012;Amodeo et al 2018).…”